Hexahydrobenzyl carbonate ester of testosterone



United States Patent Ofilice 3,314,856 Patented Apr. 18, 1967 The portion of the term 01'' the patent subsequent to Oct. 2, 1979, has been disclaimed 5 Claims. (Cl. 167-74) The invention relates to the novel ester, the hexahydrobenzyl carbonate of testosterone, and to a novel process for its preparation. Additionally the invention and method of treating hyperestrogenic and hypoandrogenic disturbances in warm blooded animals.

This application is a continuation-in-part application of our copending application Ser. No. 181,896, filed Mar. 23, 1962, now abandoned. It is an object of the product, the hexahydrobenzyl carbonate androgenic disturbances.

It is an additional object of the invention to provide a method for controlling hyperestrogenic and hypoandrogenie disturbances. I

These and other objects and advantages of the invention will become obvious from the following detailed description.

The hexahydrobenzyl carbonate of testosterone of the invention has the formula The said product has erties.

weeks in animals and clinical data with C tagged molecules has demonstrated that this activity in humans lasts for 35 to 45 days. Moreover, since the product is very soluble in oil, it can be easily administered in a single action is preferably carried out at temperatures of about 10 to about 20 0, most preferably 15 C.

Referring now to the drawings:

FIG. 1 is a graph comparing the prolonged androgenic phenyl propionate of l9-nor testosterone.

2 is a graph comparing the prolonged anabolic activity of the same two products.

The novel compositions having anabolic and androgenic activity are comprised of the hexahydrobenzyl carbonate The compositions may be in the form of oily solutions, in ampules or multiple dose fiacons, in the form of implants and as suppositories.

The novel method of inducing anabolic and androgenic activity in warm blooded animals comprises administering an eifective amount of hexahydrobenzyl carbonate of testosterone to the animal. The said product may be administered by transcutaneous methods, by intramuscular or subcutaneous injections or by rectal methods. adult is between to 500 mg. administered by subcutaneous or intramuscular methods in a single massive dose.

In the following example there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

EXAMPLE Step A: Preparation of hexahydrobenzyl chloroformate Phosgene was allowed to bubble for a period of an hour and a half into cc. of anhydrous ether cooled to 0 C. Then 30 g. of hexahydrobenzylic alcohol prepared according to Bailey, J. Am. Chem. Soc., 1955, 77, p. 358

were introduced. The reaction mixture was: agitated at 0 C. for a period of 24 hours. Next the phosgene was occurred in the form of a colorless liquid, miscible in the usual organic solvents. Its boiling point at 2 mm. was 50 C.:l and its index of refraction was n =1.457i0.00025 This product is not described in the literature.

Step B: Preparation of the hexahydrobenzyl carbonate of testosterone The temperature was maintained at 15 C. and the agitation was continued for four hours.

The resulting reaction mixture was poured with strong of testosterone. The raw product was redissolved in 800 cc. of light petroleum ether and crystallization was etfected by cooling to C. After cooling for two hours, the precipitate was separated by filtration, triturated with iced light petroleum ether, washed three times with the same solvent and then dried at 45 C. to obtain 438 gm. (73.6% yield) of the hexahydrobenzyl carbonate of testosterone having a melting point of 82 C. The product was recrystallized in light petroleum ether to obtain 407 gm. of product having a melting point of 85 to 86 C. and a specific rotation [a] =+85- tl (c.=0.5% in ethanol). The petroleum ether mother liquors were worked up to obtain a second and third yield of crystals bringing the total yield to 86.5%.

Table I shows that hexahydrobenzyl carbonate of testosterone shows an immediate androgenic and anabolic activity superior to or equal to the immediate activity of the prior art androgenic and anabolic agents.

B. Speed of saponification The speed of saponification of cyclohexyl carbonate of testosterone and hexahydrobenzyl carbonate of testosterone was determined in an acetone-water media in the presence of sodium hydroxide at 20 C. The amount of testosterone freed by saponification was determined colorimetrically by a colored reaction based on the condensation of testosterone with dinitrobenzyl chloride and the U.V. Spectrum (ethanol) 15 appearance of a red coloration upon the addition of a solution of piperazine hydrate in dimethylformamide. =389 .393 6 :16 650 to 16 800 The intensity of the coloration was determined spectrophotometrically at 515 mn by reference to a control block A 241 m and correlatively the same reaction was effected with 20 known quantities of testosterone. The results are sum- The product occurred in the form of colorless, odormanzed m Table less prismatic crystals soluble in acetone, benzene, chloroform, alcohol and ether, slightly soluble in light petro- TABLE II leum ether and insoluble in water.

Itercenftcsaploiktxifieal- T v H Ife}li0e11% sciaptrnficaltion 10110 YOO exy 1me111 OlllS 0 8X37 y IO enzy C3,!- PHARMACOLOGICAL DATA Carbonate of bonate of Testosterone Testosterone A. Determination of the immediate androgenic and ff/ anabolic activity 8 4 20 12 7 34 The tests were effected according to the Hershberger 23 iii, 85 technique (Proc. Soc. Exp. Biol. Med, 1953, vol. 83, p. 91 72 95 175) slightly modified. It consisted of a daily ad ministration-of the compound to be studied to male rats castrated at the age of 3 /2 weeks. The rats were treated for a pe- 35 mod of 10 days starting the day after the Castration and It can be easily seen from Table II that unexpectedly were sacrificed on the 11th day 22 to 26 hours after the the hexahydrobenzyl carbonate of testosterone possesses last administration. They were autopsied and the organs 2 very high rate of saponification. The said ester because of interest were separated and weighed, in particular, the of its high molecular weight would be expected to saponlifter muscle of the anus (levator ani) for the study of the ify slowly. This high rate of saponification is manifested anabolic activity and the ventral prostate and the seminal in animals by an immediate intense activity even at low vesicules for the study of the simultaneous androgenic doses as seen by the Hersheberger test in part A. effect.

The products tested were administered subcutaneously C, D i ti of prolonged activity in a volume of 0.2 cc. per rat in solution in olive oil containing 5% benzyl alcohol. The products tested were The test of prolonged activity was determined accordthe hexahydrobenzyl carbonate of testosterone, Durabolin ing to the technique of Sakamoto et al. (Proc. Soc. Exp. (phenyl propionate of 19-nor-testosterone), Dianabol Biol. Med, 1951, vol. 76, p. 406). Lots of five male rats, (17ot-methyl-A -testosterone) and Prirnobolan (l-methylcastrated at the age of 4 /2 weeks, received a single sub- N-androstene-l7fi-ol-3-one-17-acetate) and the total doses cutaneous injection in a volume of 1 cc. of the products administered were 100 500 and 1000 The results to be tested at the age of 7 /2 weeks. The animals were obtained are summarized in Table I. sacrificed at controlled dates; 10, 17, 24, 31 and 38 days TABLE 1 Weight Fresh Dried Dried Compound Dosage Weight of rats Fresh kidkid- LAF, LAF, LAS, LAS Seminal administered 1117 of rats last day kidneys, neys, neys, 111g. gJkg. rng. gJkg'. vesicules 1st day ottreatneys, g./kg. mg. g./kg. per rat per rat merit mg. per rat per rat Controls 51 97 468 4.32 99.7 1. 02 19.4 0.201 4.2 0. 043 Hexahydrobeuzylcar- 100 52 94 509 5.48 106.0 1.14 33.4 0.366 6.4 0.069 127 bonate of testosterone. 500 51 99 512 5.14 111 1.12 60.7 0.606 12.9 0.128 290 1,000 51 102 531 5.20 115 1.12 68.1 0. 682 15.1 0.147 339 Durabolin 100 51 106 545 5.16 116 1.10 49.3 0.465 10.5 0. 099 43 500 51 86 463 5.41 100 1.17 45.6 0.529 10.1 0.117 200 1,000 51 96 496 5.13 108 1.13 61.2 0.630 12.9 0.133 238 Primobolan 100 51 94 445 4.74 96 1.03 39.1 0.431 8.4 0.092 47 500 51 101 542 5.34 115 1.13 49.6 0.490 9.6 0.095 123 1,000 51 88 433 4.97 1.09 61.0 0.702 13.7 0.154 190 1315551501 51 100 478 4.77 102 1.02 20.4 0. 207 3.8 0. 097 500 51 93 499 5.39 1.17 29.8 0.320 6.1 0. 065 51 104 538 5.19 1.11 30.6 0.293 6.4 0.062

TABLE III Weight of rats at the day of- Duration of treatment days:

Controls A nor-testosterone (12.5 mg.) which is sold commercially as a delayed androgenic-anabolic agent. The lots of five animals were sacrificed and autopsied as before 31, 38, 45, 52 and 59 days after the treatment began. The results obtained have been plotted as graphs in FIGS. 1 and 2. The prolonged androgenic and anabolic activity of hexahydrobenzyl carbonate of testosterone is clearly superior to phenylpropionate of testosterone and lasts for a period of at least 16 Weeks.

Determination of acute toxicity The tests of acute toxicity were made on mice of the Rockland strain Weighing between 18 and 22 grams. Hexahydrobenzyl carbonate of testosterone was dissolved in an oily solvent and injected by subcutaneous methods into a lot of 10 mice at a dose of 150 mg./kg. The animals were held under observation for a period of a Week We claim: 1. The hexahydrobenzyl carbonate of testosterone.

Dry Levator Ani Seminal vesieules Prostate 2. A composition having prolonged anabolic and anogenic activity which comprises to 500 mg. of the hexahydrobenzyl carbonate of testosterone and a major amount of a pharmaceutical carrier.

3. The composition of claim 2 wherein the pharmaceutical carrier is an oily solvent.

4. A method of inducing prolonged androgenic and anabolic activity in warm blooded animals which comprises administering to the animals in a single close an effective amount of the hexahydrobenzyl carbonate of testosterone.

5. The method of claim 4 wherein the elfective amount for humans is 100 to 500 mg. to the adult.

References Cited by the Examiner LEWIS GO'ITS, Primary Examiner. HENRY A. FRENCH, Assistant Examiner. 

2. A COMPOSITION HAVING PROLONGED ANABOLIC AND ANDROGENIC ACTIVITY WHICH COMPRISES 100 TO 500 MG. OF THE HEXAHYDROBENZYL CARBONATE OF TESTOSTERONE AND A MAJOR AMOUNT OF A PHARMACEUTICAL CARRIER. 